Cardiovascular defects are the most common birth defects in children and a major cause of death in infants under one year of age. Since most congenital cardiovascular defects are structural, involving abnormalities in the cardiac chambers, valves, or great vessels, surgical intervention is required to repair holes, reconnect abnormal vessels and reconstruct valves to achieve normal physiology. Surgery is also necessary to treat acquired cardiovascular diseases in adults, including valve pathology secondary to degenerative or rheumatic heart disease, ventricular septal or free-wall rupture following myocardial infarction, and aortic dissection.
Open heart surgery typically relies on a suture-based closure or attachment of cardiovascular structures; however, this can be technically challenging due to the fragility of young infant tissue and diseased/damaged adult tissue, leading to longer operative times, increased risk of complications of bleeding or dehiscence, and therefore worse outcomes. Furthermore, cardiopulmonary bypass (CPB) is required for open-heart surgery, which can have significant adverse effects, including an inflammatory response and potential neurological complications.
While catheter-based interventions for closure of cardiac defects (e.g. atrial and ventricular septal defects (ASDs and VSDs)) have recently emerged in an effort to reduce the invasiveness of the procedures, major challenges remain with securing devices inside the beating heart. Fixation of devices for catheter-based closure of cardiac septal defects currently relies on mechanical means of gripping tissue. This can cause injury to critical structures, such as heart valves or specialized conduction tissue. Furthermore, if inadequate tissue rims exist around defects, the prosthesis may dislodge, damaging the neighboring structures and also leaving residual defects, limiting device application. Therefore, such methods can only be applied in select patients, depending on the anatomic location and the geometric shape of the defect.
Soft and compliant tissue adhesives that cure rapidly, have significant adhesive strength, and work in the presence of blood offer a potential solution. They could be used to attach tissue surfaces together or prosthetic devices to tissue without the need for mechanical entrapment or fixation, thereby avoiding tissue compression and erosion, and may also be utilized in minimally invasive surgical procedures. Such materials could find a broad range of applications not only in minimally invasive cardiac repair, but also in the repair of soft tissues, potentially with minimal scarring and damage. For example, in vascular surgery, suture-based anastomosis does not always result in an instantaneous hemostatic seal, and can create irregularities in the endothelium that predispose to thrombosis. Furthermore, the presence of permanent sutures can cause a foreign body reaction with further inflammation and scarring at the repair site, which may increase the risk of late vessel occlusion. Tissue adhesives could accomplish such repairs with an instantaneous seal and with minimal scarring or tissue damage.
An ideal tissue adhesive, especially for cardiovascular and/or gastrointestinal applications, should have the following properties: (1) low viscosity or liquid-like properties prior to curing to enable easy application to a desired area, (2) minimum washout by body fluids and activation only when desired to facilitate delivery and repositioning of implanted devices during minimally invasive procedures, (3) significant adhesive strength, especially in the presence of blood and/or other body fluids, (4) ability to resist the mechanical loads from adhesion to highly mobile tissue (e.g. contractions of the heart, or pulsations in large vessels), (5) ability to form a hemostatic seal, (6) minimal inflammatory response, and (7) biodegradability, which is especially important for pediatric applications since the long-term consequences of foreign materials in the growing body are uncertain.
Unfortunately, current clinically-available adhesives, such as medical grade cyanoacrylate (CA) or fibrin sealant, are easily washed out under dynamic conditions, are toxic and therefore cannot be used internally, and/or exhibit weak adhesive and/or physical strength under physiological conditions, so that they cannot withstand the forces inside the cardiac chambers and major blood vessels. Also, many of these adhesives exhibit activation properties that make fine adjustments or repositioning of the devices very difficult. Moreover, many adhesives under development achieve tissue adhesion only through chemical reaction with functional groups at the tissue surface, and thus become ineffective in the presence of blood.
Alternatives to cyanoacrylate have been explored. U.S. Pat. No. 8,143,042 to Bettinger et al. describes biodegradable elastomers that can be used for a variety of applications, such as surgical glues. The elastomers are prepared by crosslinking a pre-polymer containing crosslinkable functional groups, such as acrylate groups. The pre-polymer can have a molecular weight of between about 300 Daltons and 75,000 Daltons. The '042 patent discloses that the degree of acrylation can range from 0.3 to 0.8 and defines “low degree of acrylation” as 0.31 and “high degree of acrylation” as 0.41.
The crosslink density can affect the mechanical properties and/or adhesive strength of the crosslinked/cured polymer. The '042 patent discloses that when the pre-polymers described therein are used as a surgical glue or sealant, the crosslink density in the cured polymer, i.e. the percent of activated functional group on the corresponding pre-polymer backbone, is preferably low, less than 1%, in order to increase the number of free-hydroxyl groups and render the product exceedingly sticky. The '042 patent discloses that it is desirable to increase the number of free hydroxyl groups on the polymer in order to increase the stickiness of the polymer. This suggests that the primary mechanism of adhesion of the polymer disclosed in the '042 patent, as many other adhesives in the art, is chemical interactions between functional groups (e.g. free hydroxyl groups) on the polymer and the tissue to which it is applied. This type of chemical interaction becomes ineffective in the presence of body fluids, especially blood (Artzi et al., Adv. Mater. 21, 3399-3403 (2009)).
Similarly, Mandavi, et al., PNAS, 2008, 2307-2312 describes nanopatterned elastomeric PGSA polymer with a thin layer of oxidized dextran with aldehyde functionalities (DXTA) to increase adhesion strength of the adhesive by promoting covalent cross-linking between terminal aldehyde group in DXTA with amine groups in proteins of tissue.
This adhesion mechanism based essentially on covalent bonding between the radicals generated during the curing process and functional groups of the tissue has several limitations. The use of adhesives with reactive chemistry requires tissue surfaces to be dried prior to application of the pre-polymer, which makes it very challenging to use in cardiac application, such as during emergency procedures. Additionally, reactive chemistry can denature proteins or tissue and promote undesirable immune reaction such as local inflammation that can lead to adhesive rejection. Moreover, reactive chemistry that only bonds to the surface of tissue would likely have lower adhesion as the interface would be more distinct, and thus there would be a mismatch in mechanical properties at the interface between the glue and tissue.
There exists a need for an improved tissue sealant/adhesive that can be readily applied to the desired site, remains in place at the desired site prior to curing/crosslinking, is not washed away by bodily fluids, is biocompatible (non-toxic), and exhibits strong adhesive forces, such as those encountered inside the cardiac chambers and major blood vessels even in the presence of bodily fluids, such as blood.
Therefore, it is an object of the invention to provide improved tissue sealants/adhesives that can be readily applied to the desired site and remain in place at the desired site prior to curing/crosslinking and are not washed away by bodily fluids.
It is a further object of the invention to provide these improved tissue sealants/adhesives that are biocompatible (non-toxic).
It is also an object of the invention to provide these improved tissue sealants/adhesives that exhibit strong adhesive forces and withstand mechanical disruption, such as those encountered inside the cardiac chambers and major blood vessels.
It is an additional object of the invention to provide methods of making these improved tissue sealants/adhesives and methods of using improved tissue sealants/adhesives.